Category Archives: Helicobacter pylori

A growing body of evidence in the scientific literature supports the hypothesis that H pylori may alter epithelial tight junctional components and disrupt gastric barrier function, and that these effects may be strain-dependent. While studies in human subjects have yielded controversial findings on this topic, H pylori has the ability to increase the passage of food antigens across the gastric epithelium. This mechanism may represent a common route towards the development of postinfec-tious food allergies, which have been reported in association with H pylori as well as other enteric pathogens. H pylori is considered a class 1 carcinogen. Cell adhesion and polarity are often lost during carcinogenesis, and a role for the loss of specific claudins in these events has been suggested. buy asthma inhaler

Signalling pathways of H pylori-induced loss of barrier function
H pylori activates a broad range of signalling molecules, including protein kinase C (PKC), ERK and p38. These kinases have been shown to contribute to barrier malfunction and/or MLC phosphorylation in several in vitro models, and the fact that MAPKs may also be implicated in cancer progression further underscores the possible links between these abnormalities. Figure 3 illustrates possible signalling pathways through which H pylori may disrupt tight junctional function via MLC. It is not clear whether H pylori may increase gastric permeability via signalling cascades associated with PKC, ERK or p38. In addition, while H pylori is known to activate the small Rho-GTPase, it is not known whether this leads to MLC phosphorylation and impaired epithelial barrier function. Findings from a recent study suggest a key role for Src homology 2 domain-containing protein-tyrosine phosphatase (SHP-2) in H pylori CagA-mediated signalling in adenocarcinoma gastric stomach cells.

Similarly, the significance of cell signalling events such as Rho-kinase-mediated events to functional parameters of epithelial barrier require further investigation. Unquestionably, microbes have evolved elaborate strategies to bypass the tight junction, including mechanisms independent of MLCK. Direct binding of microbes to tight junctional elements for example may disrupt the tight junctions and increase permeability. Examples include coxsackie B virus and adenovirus, which bind to their tight junctional receptor (coxsackie virus and adenovirus receptor), which is located between other tight junctional proteins and E-cadherin. Similarly, Clostridium perfringens toxin attaches to claudin-3 via its carboxyl terminus, which in turn leads to junctional disruptions via signalling events that have yet to be uncovered.

Loss of epithelial barrier function: Signalling events Molecular signalling of epithelial permeability is a fast-growing field of investigation. Studies have found that integrin-mediated cell migration was mediated by MLCK, following a cascade of events in which Ras, extracellular signal-regulated kinase (ERK), and mitogen-activated protein kinase (MAPK)/ERK serve as essential downstream effectors. However, signalling events implicated in the MLC-dependent regulation of epithelial tight junction and barrier function, particularly in the gastric mucosa, are less clear. A variety of cellular events are associated with the epithelial abnormalities caused by H pylori, including apoptosis, cytoskeletal and tight junctional alterations, and loss of barrier function. buy ortho tri-cyclen online

It has been well-established that the paracellular permeability offered by tight junctions could be altered in response to physiological and pathological stimuli . Recent reports indicate that a variety of pathogens may actively disrupt epithelial barrier function by subverting cellular pathways, including those that lead to the activation of MLCK. As illustrated in Table 1, these effects are commonly mediated via microbial toxins and/or proteases. Interestingly, a recent study has found that a membrane permeant inhibitor of MLCK was able to inhibit the tight junctional disruptions induced by enteropathogenic Escherichia coli (EPEC) or TNFa and IFNy. In view of the implication of TNFa, a Th-1 cytokine, in the modulation of barrier function, and the significance of Th-1-mediated pathogenesis during H pylori infections, these findings may provide fertile ground from which to develop a new class of therapeutic agents targeting the loss of gastrointestinal barrier function. buy ortho tri-cyclen

Loss of epithelial barrier function: The role of myosin light chain kinase
The gastric epithelium acts as a selective barrier that prevents potentially harmful luminal agents (eg, microbial products, food antigens, toxins) from penetrating underlying tissues, while allowing for exchanges of ions and small molecules . Tight junctions and adherens junctions between gastric epithelial cells play a key role in this barrier function, and consist of a complex interaction among several protein families. Tight junctions can easily be recognized under transmission electron microscopy. birth control pills

Matrix metalloproteinases (MMP), a family of enzymes associated with inflammatory processes and capable of degrading components of the extracellular matrix, have become intriguing candidates on the list of potential markers of oncogenesis. For example, MMP-7, also called matrilysin, is found in high concentrations within premalignant gastric ulcers as well as in pancreatic intraepithelial neoplasia implying that, in addition to its role in host defense and tissue remodelling, this enzyme may also be an early marker of carcinogenesis. Clearly, additional research is needed to establish a cause-to-effect relationship in this interaction. While MMP-7 expression is known to increase in response to H pylori infection , a potential relationship with defects in epithelial barrier structure and function has yet to be established.

Loss of epithelial barrier function: The role of claudins and matrix metalloproteinases
While the majority of H pylori micro-organisms swim in the mucus layer coating the gastric epithelium, approximately 10% eventually adhere to the epithelial cells . H pylori attachment to epithelial cells alters the outcome of infection. Using a murine model of infection, a recent study observed that in the gastric mucosa, the mucus cell exhibits the greatest transcriptional response to H pylori. Subsequent cellular alterations implicate genes that broadly regulate inflammation, angio-genesis, iron metabolism and tumour suppression. Loss of cell-to-cell adhesion is a well-established precursor of gastric adenocarcinomas, and abnormalities of the adherens junctional protein E-cadherin have been found to contribute to this phenomenon as well as to the migratory potential of tumour cells. In keeping with these findings, functional inhibition of E-cadherin through mutations initiates gastric tumourigenesis.

There is growing evidence that, in addition to being unable to clear the infection, the T helper cell (Th)-1 polarity of the host response to H pylori infection contributes to the development of disease in the host. Production of Th-1 cytokines, including interferon gamma (IFNy), tumour necrosis factor alpha (TNFa) and interleukin-1beta (IL-1P) are increased during H pylori infection, which in turn amplifies the inflammatory response. IL-1 P is also a potent inhibitor of gastric acid secretion . Interestingly, polymorphisms in the human IL-1 loci, which are implicated in the increased IL-1 P production, are also associated with hypochlorhydria and gastric cancer in patients infected with H pylori. Several reports have suggested that the host Th-1 response to the infection may contribute to the carcinogenic effects of the bacterium.